Two ocellaris clownfish, Marlin and his wife Coral, are admiring their new home in the Great Barrier Reef and their clutch of eggs. A Barracuda eats Coral and knocks Marlin unconscious. He wakes up to find Coral and all but one of the eggs missing. Marlin names this last egg Nemo, a name that Coral liked.
Nemo develops a small right fin due to damage to his egg from the attack, which limits his swimming ability. After Marlin humiliates Nemo during a school field trip, he sneaks away from the reef and is captured by scuba divers. As the boat departs, one of the divers accidentally knocks his diving mask overboard. While attempting to save Nemo, Marlin meets Dory, a good-hearted and optimistic regal blue tang with short-term memory loss. Marlin and Dory encounter three sharks: Bruce, Anchor and Chum in an old minefield. Marlin discovers the diver's mask and notices an address written on it. When he argues with Dory and accidentally gives her a nosebleed, the blood scent causes Bruce to enter a feeding frenzy. The pair escape from Bruce but the mask falls into a trench in the deep sea.
During a hazardous struggle with an anglerfish in the trench, Dory sees the diving mask and reads the address located in Sydney, Australia. After receiving directions to Sydney from a school of moonfish, Marlin and Dory encounter a bloom of jellyfish that nearly kills them. Marlin loses consciousness and wakes up to see a sea turtle named Crush, who takes Dory and him on the East Australian Current. Marlin shares the details of his journey with a group of young sea turtles, his story is spread across the ocean, and he finds Nemo in Sydney.
Nemo's captor - P. Sherman, a dentist - places him in a fish tank in his office on Sydney Harbour. He meets aquarium fish called the Tank Gang, led by a moorish idol named Gill, who has a broken fin. The Tank Gang includes Bloat, a puffer fish; Bubbles, a yellow tang; Peach, an ochre starfish; Gurgle, a royal gramma; Jacques, a pacific cleaner shrimp; and Deb, a blacktailed humbug.
The fish learn that Sherman plans to give Nemo to his niece, Darla, who once killed a fish by constantly shaking its bag. Gill reveals his escape plan, which involves jamming the tank's filter, forcing the dentist to remove the fish in order to clean it. The fish would be placed in plastic bags, and they would roll out the window and into the harbor. After a brown pelican named Nigel brings news of Marlin's adventure, Nemo jams the filter, but the dentist installs a new high-tech filter.
Upon leaving the East Australian Current, Marlin and Dory are engulfed by a whale. Inside the whale's mouth, Dory communicates with the whale, which carries them to Port Jackson and expels them through his blowhole. They are met by Nigel, who recognizes Marlin from the stories he has heard and takes them to the dentist's office. Darla has arrived and the dentist is giving Nemo to her. Nemo tries to play dead to save himself as Nigel arrives. Marlin sees Nemo and believes he is dead. Gill helps Nemo escape into a drain. In despair, Marlin leaves Dory and begins swimming home. Dory loses her memory and becomes confused, but meets Nemo, who reached the ocean. Dory's memory is restored after she reads the word "Sydney" on a nearby drainpipe. She guides Nemo to Marlin and reunite. Dory is caught in a fishing net with a school of grouper. Nemo enters the net and directs the group to swim downward to break the net, enabling them to escape. After returning home, Nemo leaves for school and Marlin, no longer overprotective, proudly watches Nemo swim away with Dory at his side.
At the dentist's office, the high-tech filter breaks down and the Tank Gang escapes into the harbor, belatedly realizing they are still confined in the bags of water.